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Welcome to Ed's Pathology Notes, placed
here originally for the convenience of medical students
at my school. You need to check the accuracy of any
information, from any source, against other credible
sources. I cannot diagnose or treat over the web,
I cannot comment on the health care you have already
received,
and these notes cannot substitute for your
own doctor's care. I am good at helping people find
resources and answers. If you need me, send me an
E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.
No texting or chat messages, please. Ordinary e-mails are welcome.

I'm still doing my best to answer
everybody.
Sometimes I get backlogged,
sometimes my E-mail crashes, and sometimes my
literature search software crashes. If you've not heard
from me in a week, post me again. I send my most
challenging questions to the medical student pathology
interest group, minus the name, but with your E-mail
where you can receive a reply.

Numbers in {curly braces} are from the magnificent
Slice
of Life videodisk. No medical student should
be without access to this wonderful resource.

I am presently adding clickable links to
images in these notes. Let me know about good online
sources in addition to these:

Freely have you received, freely give. -- Matthew 10:8. My
site receives an enormous amount of traffic, and I'm
still handling dozens of requests for information weekly, all
as a public service.

Pathology's modern founder,
Rudolf
Virchow M.D., left a legacy
of realism and social conscience for the discipline. I am
a mainstream Christian, a man of science, and a proponent of
common sense and common kindness. I am an outspoken enemy
of all the make-believe and bunk that interfere with
peoples' health, reasonable freedom, and happiness. I
talk and write straight, and without apology.

Throughout these notes, I am speaking only
for myself, and not for any employer, organization,
or associate.

Special thanks to my friend and colleague,
Charles Wheeler M.D.,
pathologist and former Kansas City mayor. Thanks also
to the real Patch
Adams M.D., who wrote me encouragement when we were both
beginning our unusual medical careers.

If you're a private individual who's
enjoyed this site, and want to say, "Thank you, Ed!", then
what I'd like best is a contribution to the Episcopalian home for
abandoned, neglected, and abused kids in Nevada:

Especially if you're looking for
information on a disease with a name
that you know, here are a couple of
great places for you to go right now
and use Medline, which will
allow you to find every relevant
current scientific publication.
You owe it to yourself to learn to
use this invaluable internet resource.
Not only will you find some information
immediately, but you'll have references
to journal articles that you can obtain
by interlibrary loan, plus the names of
the world's foremost experts and their
institutions.

Alternative (complementary) medicine has made real progress since my
generally-unfavorable 1983 review. If you are
interested in complementary medicine, then I would urge you
to visit my new
8Alternative Medicine page.
If you are looking for something on complementary
medicine, please go first to
the American
Association of Naturopathic Physicians.
And for your enjoyment... here are some of my old pathology
exams
for medical school undergraduates.

I cannot examine every claim that my correspondents
share with me. Sometimes the independent thinkers
prove to be correct, and paradigms shift as a result.
You also know that extraordinary claims require
extraordinary evidence. When a discovery proves to
square with the observable world, scientists make
reputations by confirming it, and corporations
are soon making profits from it. When a
decades-old claim by a "persecuted genius"
finds no acceptance from mainstream science,
it probably failed some basic experimental tests designed
to eliminate self-deception. If you ask me about
something like this, I will simply invite you to
do some tests yourself, perhaps as a high-school
science project. Who knows? Perhaps
it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship
by suspending their own reasoning and
simply accepting a single authority that seems wise and good.
I've learned that they leave the movements when, and only when, they
discover they have been maliciously deceived.
In the meantime, nothing that I can say or do will
convince such people that I am a decent human being. I no longer
answer my crank mail.

This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.

During the eighteen years my site has been online, it's proved to be
one of the most popular of all internet sites for undergraduate
physician and allied-health education. It is so well-known
that I'm not worried about borrowers.
I never refuse requests from colleagues for permission to
adapt or duplicate it for their own courses... and many do.
So, fellow-teachers,
help yourselves. Don't sell it for a profit, don't use it for a bad purpose,
and at some time in your course, mention me as author and William Carey as my institution. Drop me a note about
your successes. And special
thanks to everyone who's helped and encouraged me, and especially the
people at William Carey
for making it still possible, and my teaching assistants over the years.

Whatever you're looking for on the web, I hope you find it,
here or elsewhere. Health and friendship!

In my notes, the most helpful current
journal references are embedded in the text.
Students using these during lecture strongly prefer this.
And because the site is constantly being updated,
numbered endnotes would be unmanageable.
What's available online, and for whom, is always changing.
Most public libraries will be happy to help you get an article
that you need. Good luck on your own searches, and again,
if there is any way in which I can help you, please contact me at
scalpel_blade@yahoo.com.
No texting or chat messages, please. Ordinary e-mails are welcome.
Health and friendship!

Define "tumors" and "neoplasms". Tell why they are important. Define "oncology". Tell how
tumors are like organs, and how they are different.

Distinguish "benign tumors" and "malignant tumors" by their gross and microscopic appearances
and their behaviors. Tell what "well-differentiated" and "poorly differentiated" mean. Tell how
benign tumors can cause problems.

Define "cancer", "malignant", and "metastasis". Tell what any cancer will ultimately do to the
patient if it is not cured. Recognize the typical appearances of cancers. Distinguish "carcinomas"
and "sarcomas".

Tell how and where various cancers tend to metastasize. Describe patterns for invasion and
metastasis by various malignant tumors.

List the three most common cancers in men and in women, and the three most common fatal ones.

Given a tumor name, name the cell of origin and describe the behavior. Given the cell of origin (or
a hint) and the behavior (or a hint), name the tumor.

Distinguish "grade" and "stage" of a cancer. Tell why these numbers are important.

Recognize, under the microscope, a squamous cell carcinoma, an adenoma, an adenocarcinoma, a
tumor of hematologic origin, and a spindle cell sarcoma. Recognize anaplasia, and generally tell
benign from malignant tumors.

Critique the following statement, overheard on a cancer ward: "Cancer cells grow faster than normal
cells and are not under the body's control. Therefore, the treatment for cancer involves giving
anti-mitotic drugs that kill fast-growing cells."

Cancers (malignant neoplasms) invade and spread to remote sites (metastasize).
The original tumor is called the PRIMARY.

Benign tumors
cannot invade or spread to remote sites, but they can cause problems by compressing local
structures.

Tumors arise from single cells, and they recapitulate, more or less, the things that cell did in health.
The cell of origin gives its name to the tumor.

Benign tumors are usually round like balls. Cancers look like cauliflowers, ulcers, or else simply
expand the organ.

Cancers that arise from epithelium are called "carcinomas". Cancers
that arise from mesenchyme/mesoderm are called "sarcomas".

Most cancers arising from ectoderm and endoderm are carcinomas, since
these cells primarily become surface epithelium and gland parenchyma.

Of course, ectoderm is also the source of nervous tissue, but tumors
arising here are less common than carcinomas.

Cancers arising from mesoderm can be carcinomas (i.e., adrenals, genitourinary),
sarcomas (solid connective tissue and all sorts of muscle), or cells of
hematopoietic origin (leukemias, lymphomas).

Both the appearance of the individual cells
and the histologic architecture in benign tumors are similar to normal histology. Cells and
microscopic architecture in cancers are bizarre. The grade of a cancer is a function of how bizarre
the cells look. The higher the grade, the more likely to cancer is to behave aggressively.

One out of about every five persons in the US who die this year will die of tumors (about 500,000
total).

For the foreseeable future, all tumor diagnoses will be made by us anatomic
pathologists, using conventional light microscopy as our primary tool.

All of the 1.3 million patients with cancer in the USA will be diagnosed
by pathologists; many million more people will have biopsies that will turn out
"no cancer." Overall, we pathologists do a pretty good job. Please remember these commonplaces
(CA 60: 139, 2010): (1) If you miss the tumor on your biopsy,
we can't diagnose it; (2) If the diagnosis we report doesn't match what
you think it is, come talk with us about it; (3) If I were a clinician,
I'd insist that there be two different pathologists' signatures on every positive cancer biopsy.

* DNA microarray technology, while fascinating, is still
almost exclusively a research tool. See Am. J. Path. 171: 375, 2007.

"unnatural"--pus, nodule of healing bone at a fracture site ("callus")

"contrary to nature"--what we now know as neoplasms ("new growths")

The ancient medical writings show an awareness of cancer,
and Morgagni remarked that by his era, most physicians were
aware that tumors were not treatable except by surgery.

"Oncology" is the study of tumors. In current usage, an oncologist is an internist or surgeon who
specializes in the administration of cancer chemotherapy.

In modern usage, a TUMOR/NEOPLASM (the words are exact synonyms) may be thought of as an attempt by the body under some
stimulus to make some new sort of organ. It develops in the wrong shape, in the wrong place, and it
persists after the initiating stimulus is removed.

Tumors are LIKE organs:

All have parenchyma and stroma.

Cells usually look similar to cells in the organ where the tumor arose.

Cells will continue to perform some of the functions of the parent organ
and express most of the same proteins.

Tumors are DIFFERENT from organs:

They don't contribute to the homeostasis of the body.

They usually grow more rapidly than surrounding tissues.

Some benign and all malignant tumors never cease to grow.

When a benign tumor "ceases to grow", it simply means that the number
of cells dying off equals the number of new cells. Since the genome
of malignant tumors is by definition destabilized, more-and-more
actively-proliferating clones of cells appear, so continued growth is
inevitable.

"Spontaneous regression" of a cancer (i.e., massive shrinkage or
disappearance without adequate therapy to explain it) is much-discussed
phenomenon that occasionally happens.
More often than not, the cancer
comes back after a few months.
The phenomenon is fairly well known in CNS lymphomas (Neurology 59:
762, 2002) and melanomas (areas of "partial regression"
are often seen in the primary; Am. J. Clin. Path. 124: 37, 2005; it's a good
prognostic indicator J. Clin. Path. 61: 297, 2008; one metastasized
melanoma in 400 will spontaneously regress Melanoma Res. 18: 279, 2008;
also Am. J. Dermpath. 30: 178, 2008);
the basis (especially in the latter) is almost certainly an immune attack.
If there are metastases, they may or may not also disappear.

A few pediatric cancers, notably neuroblastoma, often self-cure.
They all arise from cells that are programmed to die anyway as the child gets older.
More about this later.

Testicular carcinomas often present as metastases, with the primary
no longer detectable except perhaps as a scar (Am. J. Surg. Path. 30: 858, 2006;
J. Urol. 182:
2303, 2009 -- take it anyway as there's likely to be viable cancer).

* You may hear more in the future about the "abscopal" / "distant bystander effect",
in which local treatment (radiation or otherwise) results in regression
of distant tumor masses "due to immunity". Controversial. See Cancer Treatment Reviews 31:
159, 2005; J. Clin. Path. 62: 647, 2009.

Malignant: A neoplasm that will invade the surround tissue.
A synonym for "malignant neoplasm" is "cancer".
Most
types of cancer will also eventually spread to remote sites;
hence the importance of timely detection and cure.

Benign: (1) A neoplasm that will compress but
not invade the surrounding tissue. (2) Loosely, any non-cancer,
non-precancer diagnosis.

However, no malignant tumor grows as rapidly as an embryo, nor do cancer cells divide nearly as
fast as cells in normal bone marrow or intestinal epithelium. Today, anyone who thinks of cancer
cells growing "without any control" is guilty of willful ignorance

Cells differ morphologically and functionally from normal cells, and tumor architecture is less
organized than that of parent tissue.

Tumor cells are locally invasive; the tumor grows into the surrounding tissue and destroys it.

This feature led Dr. Hippocrates to call such tumors karkinoma after
karkinos, Greek for "crab."
(Cancer is Latin for "crab".)

The tumor will eventually metastasize, spreading to another site remote from the original tumor
(exceptions: basal cell carcinomas of skin, cancers of glial origin).

MALIGNANT TUMOR and CANCER are synonyms.

Benign or malignant, each tumor has a "cell of origin" from its tissue.

Old studies proved that women heterozygous for G6PD variants express only one form in each
uterine tumor because of lyonization. And we've long known that plasma cell myeloma produces a
monoclonal immunoglobulin product. More about
"Nowell's law" soon.

Tumor cells almost always mimic one cell type of some normal organ, usually the one in which the
tumor arose.

The resemblance will be better or worse depending on whether the tumor is "well-differentiated" or
"poorly differentiated."

Much of the day-to-day work of a surgical pathologist is figuring out the cell of origin of poorly-differentiated cancers.
The main tools are electron microscopy (now mostly passé) and
immunoperoxidase stains ("the brown revolution").

Worth learning now:

SQUAMOUS CELL CARCINOMAS

These arise anywhere there is a stratified squamous epithelium, either healthy (skin, esophagus,
mouth, many others) or metaplastic (endocervix, bronchi).

Look for any (or even all) of the following:

keratin (will stain orange-red on H&E)

pearls (i.e., whorls that mimic little hairs)

* For the truly hard-core: You'll meet non-malignant keratin pearls
again as the Hassal's corpuscles of the thymus,
the horn cysts of seborrheic keratoses, and the smelly "tonsilloliths"
that many people hock up from their tonsils.

desmosomes ("intercellular bridges", "prickles")

tonofilaments (electron microscopy)

single-cell apoptosis (cells think they're at the top of the epidermis)

Adenomas exhibit most of the same features (though not glands-within-glands or signet-ring cells),
and look benign. (An adenoma may contain dysplasia without invasion; in that case,
the adenoma is considered benign but premalignant.) See below.

SPINDLE-CELL SARCOMAS

These arise anywhere where there is connective tissue.

Look for cells with elongated nuclei running parallel, with at least a modest amount of cytoplasm.

Increased nuclear DNA (obvious on H&E; the hard-core get flow cytometry),
increased nuclear/cytoplasmic ratio, hyperchromatic nucleus,
coarsening of chromatin, wrinkled nuclear edges, macronucleoli, weird-shaped
nucleoli. Multinucleation is
a marker for cancer only if the nuclei within an individual cell are
obviously different from one another.

Numerous and bizarre mitotic figures. Tripolar mitoses
are only the most familiar of the many weird patterns you may see.
(NOTE: Mitotic figures last longer in cancers than
in healthy tissues, so this is not "proof that cancers grow very rapidly".)

There MAY also be microscopic visible INVASION (tumor cells growing into adjacent normal structures
where they don't belong), and/or indirect evidence (hemorrhage and/or necrosis; either is important
evidence that the tumor in question is malignant).

Today's pathologists have stains to show the laminin in the basement
membrane, if there is any doubt as to whether the tumor is "through".

"Intraepithelial spread" is possible and may take the form of single cells ("Paget's disease" of the
nipple from an underlying breast cancer, many melanomas) or of DYSPLASIA / CARCINOMA IN SITU, in which an
epithelial surface is replaced by a layer of anaplastic cells that has not (yet)
penetrated the basement membrane.

WHAT IS THE DIFFERENCE BETWEEN DYSPLASIA AND CARCINOMA IN SITU?

First idea: "Carcinoma in situ is full-thickness dysplasia. Turn
the epithelium upside-down. If it looks the same, it is carcinoma in situ.
The cells have completely forgotten how to mature." This merely
reminds us that going from the mildest dysplasia to the meanest
carcinoma in situ is a continuum. It's "cancer" when, and only when,
the first malignant cell manages to grow through the basement membrane --
and that means it's no longer "in situ".

Second idea: "Dysplasia is reversible and carcinoma in situ is not."
I have been hearing this since I entered medical school without anybody
ever explaining why I should believe it. How are you going to tell?
Today, some people are
managing milder cervical dysplasias "conservatively", we know the likelihood
of regression depends on the virus (Ob. Gyn. 113: 18, 2009) and what genes
are still working (J. Clin. Path. 64: 303, 2011), but still no one is leaving the high-grade
carcinoma-in-situ alone. However, nobody would "just watch" a high-grade
intra-epithelial lesion "to see whether it goes away by itself".

Third idea: "Who cares? Call them both INTRAEPITHELIAL ANAPLASIA.
Mild, moderate, or severe."
This made so much sense that Bethesda decided in the 1990's to call them "intraepithelial
neoplasia" instead. Realizing the error, their current term is "intraepithelial lesion."

Leave the arcana of grading up to us for now. Rules are constantly changing, and new
prognostic factors emerging.

TUMOR STAGE: assigned by the clinician on the basis of all available information on the extent of
tumor spread.

Stage I might mean the tumor is smaller than 1 cm diameter, without metastases

Stage II might mean the tumor is larger than 1 cm and/or is symptomatic and/or there are metastases
to the regional lymph nodes

Stage III might mean the tumor has infiltrated a non-resectable structure and/or there are distant
metastases

Rules for assigning stage are quite elaborate and different for each type of tumor.

Alternative system: TNM

"T" for tumor:

T1 might mean primary tumor is smaller than 1 cm in diameter

T2 might mean primary tumor is larger than 1 cm in diameter

T3 might mean primary tumor is invading something non-resectable

"N" for regional lymph nodes:

N0 would mean no tumor in regional lymph nodes

N1 might mean tumor in a few nearby lymph nodes

N2 might mean many nodes, or some nodes farther downstream, are involved

"M" for metastases:

M0 would mean no distant metastases

M1 would imply distant metastases, etc.

* So the TNM stage for a lung cancer that is invading or encasing the superior vena cava but has
metastases only in two nearby lymph nodes might be T3 N1 M0.

Memorizing tumor staging systems is not an appropriate pathology learning objective, and I will
not test you on it.

Generally tumors of high GRADE present at high STAGE, while tumors of low
GRADE present at low
STAGE.

Tumor Nomenclature

I. To assign a name to a tumor that you have examined, begin by writing the suffix -OMA. Most
tumor names end in this way. (Unfortunately, the suffix simply means "swelling", and some
non-neoplasms also use the suffix, i.e., GRANULOMA, HEMATOMA, XANTHOMA, traumatic NEUROMA,
and "gossypiboma" for a sponge left in after surgery Am. J. For. Med. Path. 33:
54, 2012).

II. If the tumor is MALIGNANT, write the root CARCIN- ("crab") if the tumor is of epithelial origin, or
SARC- ("flesh") if the tumor is of mesenchymal origin, before -OMA. If the tumor is
BENIGN, do not
write anything.

If the tumor originated in SQUAMOUS or UROTHELIUM (formerly
called "transitional epithelium"), is BENIGN, and protrudes above the
epithelial surface, use the root PAPILLO-. If it meets the first
two criteria but does not protrude, the pathologist knows the name but
you don't need to just now.

If the tumor originated in NON-GLANDULAR EPITHELIUM and is
MALIGNANT, name it for the cell of origin.

A POLYP describes a gross appearance rather than what's actually happening.
It might be a cancer, a benign tumor, a hamartoma, a choristoma, or a hyperplasia
such as a singer's vocal cord polyp. The term won't appear without a clarifier on
a pathology report.